Structural basis for accommodation of nonsteroidal ligands in the androgen receptor

被引:174
作者
Bohl, CE
Miller, DD
Chen, JY
Bell, CE [1 ]
Dalton, JT
机构
[1] Ohio State Univ, Coll Med & Publ Hlth, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA
[2] Ohio State Univ, Coll Pharm, Div Pharmaceut, Columbus, OH 43210 USA
[3] Univ Tennessee, Coll Pharm, Dept Pharmaceut Sci, Memphis, TN 38163 USA
关键词
D O I
10.1074/jbc.M507464200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mechanism by which the androgen receptor (AR) distinguishes between agonist and antagonist ligands is poorly understood. AR antagonists are currently used to treat prostate cancer. However, mutations commonly develop in patients that convert these compounds to agonists. Recently, our laboratory discovered selective androgen receptor modulators, which structurally resemble the nonsteroidal AR antagonists bicalutamide and hydroxyflutamide but act as agonists for the androgen receptor in a tissue-selective manner. To investigate why subtle structural changes to both the ligand and the receptor (i.e. mutations) result in drastic changes in activity, we studied structure-activity relationships for nonsteroidal AR ligands through crystallography and site-directed mutagenesis, comparing bound conformations of R-bicalutamide, hydroxyflutamide, and two previously reported nonsteroidal androgens, S-1 and R-3. These studies provide the first crystallographic evidence of the mechanism by which nonsteroidal ligands interact with the wild type AR. We have shown that changes induced to the positions of Trp-741, Thr-877, and Met-895 allow for ligand accommodation within the AR binding pocket and that a water-mediated hydrogen bond to the backbone oxygen of Leu-873 and the ketone of hydroxyflutamide is present when bound to the T877A AR variant. Additionally, we demonstrated that R-bicalutamide stimulates transcriptional activation in AR harboring the M895T point mutation. As a whole, these studies provide critical new insight for receptor-based drug design of nonsteroidal AR agonists and antagonists.
引用
收藏
页码:37747 / 37754
页数:8
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